Oncotarget

Research Papers:

Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies

Yoshiji Yamada _, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai and Masashi Tanaka

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Oncotarget. 2017; 8:80492-80505. https://doi.org/10.18632/oncotarget.19287

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Abstract

Yoshiji Yamada1,2, Jun Sakuma2,3,4, Ichiro Takeuchi2,4,5, Yoshiki Yasukochi1,2, Kimihiko Kato1,6, Mitsutoshi Oguri1,7, Tetsuo Fujimaki8, Hideki Horibe9, Masaaki Muramatsu10, Motoji Sawabe11, Yoshinori Fujiwara12, Yu Taniguchi12, Shuichi Obuchi13, Hisashi Kawai13, Shoji Shinkai14, Seijiro Mori15, Tomio Arai16 and Masashi Tanaka17

1Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan

2CREST, Japan Science and Technology Agency, Kawaguchi, Japan

3Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan

4RIKEN Center for Advanced Intelligence Project, Tokyo, Japan

5Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan

6Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan

7Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan

8Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan

9Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan

10Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

11Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan

12Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

13Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

14Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

15Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

16Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

17Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

Correspondence to:

Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp

Keywords: diabetes mellitus, fasting plasma glucose, blood glycosylated hemoglobin, polymorphism, exome-wide association study

Received: March 31, 2017     Accepted: June 09, 2017     Published: July 17, 2017

ABSTRACT

We performed exome-wide association studies to identify single nucleotide polymorphisms that either influence fasting plasma glucose level or blood hemoglobin A1c content or confer susceptibility to type 2 diabetes mellitus in Japanese. Exome-wide association studies were performed with the use of Illumina Human Exome-12 DNA Analysis or Infinium Exome-24 BeadChip arrays and with 11,729 or 8635 subjects for fasting plasma glucose level or blood hemoglobin A1c content, respectively, or with 14,023 subjects for type 2 diabetes mellitus (3573 cases, 10,450 controls). The relation of genotypes of 41,265 polymorphisms to fasting plasma glucose level or blood hemoglobin A1c content was examined by linear regression analysis. After Bonferroni’s correction, 41 and 17 polymorphisms were significantly (P < 1.21 × 10−6) associated with fasting plasma glucose level or blood hemoglobin A1c content, respectively, with two polymorphisms (rs139421991, rs189305583) being associated with both. Examination of the relation of allele frequencies to type 2 diabetes mellitus with Fisher’s exact test revealed that 87 polymorphisms were significantly (P < 1.21 × 10−6) associated with type 2 diabetes mellitus. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that four polymorphisms (rs138313632, rs76974938, rs139012426, rs147317864) were significantly (P < 1.44 × 10−4) associated with type 2 diabetes mellitus, with rs138313632 and rs139012426 also being associated with fasting plasma glucose and rs76974938 with blood hemoglobin A1c. Five polymorphisms—rs139421991 of CAT, rs189305583 of PDCL2, rs138313632 of RUFY1, rs139012426 of LOC100505549, and rs76974938 of C21orf59—may be novel determinants of type 2 diabetes mellitus.


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